LeonaBio executives and key opinion leaders (KOLs) in breast cancer outlined the company’s clinical and commercial strategy for lasofoxifene during a webcast focused on endocrine-resistant, ER-positive metastatic breast cancer—particularly tumors with ESR1 mutations. The event featured Mark Litton, president and CEO of LeonaBio; David Portmann, founder and CEO of Sermonix Pharmaceuticals; and physicians Matthew Goetz of Mayo Clinic and Seth Wander of Massachusetts General Hospital.
Company positioning and market backdrop
Litton said LeonaBio licensed development and commercialization rights to lasofoxifene “at the end of 2025,” calling the transaction a pivotal move that added a late-stage asset and positioned the company at the “intersection of endocrine biology, precision medicine, and combination therapy strategies.” He noted that ER-positive disease remains the most common metastatic breast cancer subtype, which he said accounts for roughly 70% of cases, and argued that endocrine resistance remains a significant clinical problem.
Lasofoxifene’s proposed differentiation: modulation vs. degradation
Portmann described lasofoxifene as “a potent third-generation selective estrogen receptor modulator,” emphasizing tissue selectivity as a key differentiator versus therapies designed to degrade the estrogen receptor. He said lasofoxifene modulates the receptor in a way that can spare estrogen receptor activity in tissues such as bone and urogenital tissue, and he contrasted that with complete receptor degradation or blockade, which he said can create tolerability and quality-of-life challenges.
Portmann cited co-crystallography work, saying lasofoxifene can “lock” the mutated receptor in an antagonist conformation in breast cancer cells while retaining agonist properties in tissues like bone and vaginal tissue, and he said there was no evidence of endometrial hyperplasia or cancer risks “like tamoxifen.” He also referenced prior development in osteoporosis and vulvovaginal atrophy, stating lasofoxifene improved symptoms in two phase III trials in post-menopausal vulvovaginal atrophy and showed reductions in patient-reported vaginal dryness and painful intercourse compared with fulvestrant in the ELAINE 1 study.
In discussing preclinical potency, Portmann said in vitro data showed lasofoxifene maintained potency in ESR1-mutant cell lines relative to wild-type estrogen receptor. He compared that with fulvestrant, which he said showed a “1–2 log drop in potency” in ESR1 mutations, and said lasofoxifene “outperformed both approved and investigational SERDs and other estrogen receptor antagonists with a four to 40-fold greater potency against mutated receptors.”
ELAINE trial results highlighted by speakers
Portmann reviewed phase II programs supporting the ongoing phase III effort. In ELAINE 1, a head-to-head study versus fulvestrant in post-CDK4/6 aromatase inhibitor ESR1-mutated metastatic breast cancer, Portmann said lasofoxifene monotherapy achieved median progression-free survival (PFS) of 5.6 months compared with 3.7 months for fulvestrant, with “clear separation” in Kaplan-Meier curves. He also pointed to circulating tumor DNA data, stating lasofoxifene showed clearance and decreases across ESR1 mutation variants, including Y537S.
In ELAINE 2, an open-label combination study of lasofoxifene plus abemaciclib in heavily pretreated ESR1-mutated metastatic breast cancer, Portmann said the trial showed a median PFS “approaching 13 months” and an objective response rate of 56%. Goetz later underscored that point, noting the response rate was “pretty remarkable” and that tumor shrinkage is a metric patients can relate to.
Phase III ELAINE 3 design, timing, and enrollment
Portmann said LeonaBio is enrolling the 600-patient ELAINE 3 registrational trial comparing lasofoxifene plus abemaciclib to fulvestrant plus abemaciclib, with PFS as the primary endpoint and secondary endpoints including overall survival, objective response rate, quality of life, and patient-reported outcomes. He described the design as focused on an enriched ESR1-mutated population to avoid diluting efficacy signals seen in “all-comer” designs.
Eligible patients include pre- or post-menopausal women or men who progressed after an aromatase inhibitor plus palbociclib or ribociclib and have an ESR1 mutation detected, Portmann said. He added that the study is more than halfway enrolled and expects a top-line readout in 2027. Litton later said enrollment is “going very well” and that the company is “guiding towards back end of this year to get completion of enrollment,” while describing the 2027 readout as a best estimate. Portmann noted the trial is event-driven.
Asked about an interim futility analysis, Litton said a futility analysis is contemplated, but added that it “will not be based on efficacy.”
KOL perspective: why combinations and tolerability matter
Goetz said second-line endocrine sensitivity has diminished in the era of first-line CDK4/6 inhibitors, and that oral SERDs and other ER-targeting monotherapies show “limited anti-tumor activity,” largely in the ESR1-mutant setting. He said patients are seeking better durability than typical 3–6 month PFS outcomes and often want to delay chemotherapy, making effective oral regimens important.
Wander said ESR1 mutation is “a surrogate marker for endocrine sensitivity, but it doesn’t guarantee” durable responses, and argued that doublet combinations can provide important synergy. He also praised ELAINE 3’s control arm, noting that some studies with oral SERDs lacked a doublet control, making it harder to interpret the endocrine agent’s contribution inside a combination.
On tolerability, Wander said combination strategies increase scrutiny on therapeutic windows and highlighted concerns such as bradycardia, photopsia, gastrointestinal toxicity, and cytopenias associated with some next-generation anti-estrogens. He said lasofoxifene’s tolerability profile and prior experience in bone and vaginal health could be meaningful for patients with substantial prior therapy burdens.
Regarding biomarker testing, Goetz said ESR1 and broader sequencing has become standard practice, particularly after FDA approval of ESR1-directed therapy, and is widely available through multiple testing providers.
About Athira Pharma (NASDAQ:ATHA)
Athira Pharma, Inc is a clinical?stage biopharmaceutical company headquartered in Seattle, Washington, that is dedicated to developing therapies aimed at restoring neuronal health and slowing the progression of neurodegenerative diseases. Founded in 2011, Athira’s research focuses on the Hepatocyte Growth Factor (HGF)/MET pathway as a novel mechanism to promote neuronal repair, synaptic function and overall cognitive performance. The company’s overarching goal is to offer disease?modifying treatments for conditions such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS).
The centerpiece of Athira’s pipeline is fosgonimeton (ATH?1017), a small?molecule positive modulator of the HGF/MET system.
